Role of CACNA1C in Brugada syndrome: Prevalence and phenotype of probands referred for genetic testing

Background: Evidence for the role of the CACNA1C gene, which encodes for the α-subunit of the cardiac L-type calcium channel CaV1.2, as a cause of the BrS3 variant of Brugada syndrome (BrS) is contradictory. Objective: The purpose of this study was to define in a large BrS cohort the yield of molecular screening and to test whether appropriate patient selection could improve clinical utility. Methods: A total of 709 patients were included in this study. BrS probands (n = 563, consecutively referred) underwent CACNA1C sequencing. Two matched cohorts where defined: discovery cohort (n = 200) and confirmation cohort (n = 363). In addition, the clinical phenotypes of a matched SCN5A-positive BrS cohort (n = 146) were included for comparative genotype-phenotype correlation. Results: In the discovery cohort, we identified 11 different rare variants in 9 patients; 10 of the variants (5%) were considered potentially causative based on their frequency in the general population. However, American College of Medical Genetics criteria were unable to classify the majority (80%) of them, which eventually were labeled as variants of unknown significance (VUS). Functional studies revealed a loss of function for 9 variants, pointing to a prevalence of CACNA1C causative variants in 4% of the discovery cohort. Genotype-phenotype correlation showed that pathogenic variants are significantly more frequent in patients with shorter QTc (12.9% vs 2.2% in patients with QTc <390 ms). Conclusion: CACNA1C is an infrequent but definitive cause of BrS typically associated with short QT. Functional studies are highly relevant to improve variant interpretation.